1. Field of the Invention
This invention provides compositions and methods for the treatment of cancer, and generally relates to the fields of medicinal chemistry, medicine, pharmacology, molecular biology, and biology.
2. Description of Related Art
Hypoxia activated and bioreducible drugs of antineoplastic agents are useful for treating solid tumor cancers. Such hypoxia activated drugs contain a bioreductive group, an optional linker, and an antineoplastic agent, and are less cytotoxic than the corresponding antineoplastic agents without the bioreductive group attached thereto. Under hypoxic conditions or hypoxia, the bioreductive group present in the drug is reduced, and a cytotoxic antineoplastic agent is generated and/or released. Under normoxic conditions, or normoxia, such as those existing in a normal cell, a hypoxia activated drug is typically non-toxic or at least much less toxic than under hypoxic conditions, or hypoxia. Due to insufficient vascularization of the solid tumor, certain tumor cells will exist in a hypoxic state. The cytotoxic antineoplastic agents generated and/or released from a hypoxia activated drug in the hypoxic zone of the solid tumor can selectively kill cancer cells in and around that zone.
Aryl nitrogen mustards are a class of antineoplastic agents useful in the treatment of leukemias and solid tumors. Certain aryl nitrogen mustards, such as, for example, chlorambucil and melphalan, contain a substituted phenyl moiety attached to an N,N-bis-(2-chloroethyl)amino moiety.
Heretofore, the attachment of a bioreductive group optionally though a suitable linker to these aryl nitrogen mustards to provide effective anti-tumor agents was unknown.
There remains a need for additional hypoxia activated and similar bioreducible drugs for the treatment of cancer, including those containing aryl nitrogen mustards and related antineoplastic agents. The present invention meets such needs as summarized below.